RESUMEN
N-acetylation participates in the biotransformation of hydrazine drugs and arylamine carcinogens to cytotoxic and carcinogenic products. Differences in acetylation capacity expressed in several mammalian species, including humans and mice, are associated with differences in toxicity and carcinogenicity from these chemicals. The present study examines the influence of genotype, age and sex on kidney N-acetyltransferase (NAT) activity in C57BL/6J (B6) and A/J inbred mouse strains using p-amino-benzoic acid (PABA) as a substrate. There were no strain differences in kidney PABA NAT activity. However, within these strains, males have greater kidney NAT activity than females. A 2-fold increase in kidney NAT activity of males was evident by 30 days postnatally and persisted into maturity (> 200 days after birth), whereas the kidney NAT activity of females remained unchanged. Castration reduced male kidney NAT to female levels, whereas testosterone replacement restored original levels of activity. Ovariectomized females exhibited the same enzyme activity as intact females. Testosterone increased kidney NAT activity in females, but not in intact males. Estradiol decreased kidney NAT in males, but had no effect on female NAT activity. The data suggest that the increase in kidney NAT activity in male mice that accompanies development is under androgenic control. This idea is further supported by our finding that the kidney NAT activity of androgen-insensitive tfm/y mice is significantly less than the activity of either females or males sharing the same genetic background. These observations may explain, in part, the higher susceptibility of male mice to 2-acetylaminofluorene mutagenicity and carcinogenicity.
Asunto(s)
Acetiltransferasas/metabolismo , Riñón/enzimología , Testosterona/farmacología , Ácido 4-Aminobenzoico/metabolismo , Acetilación , Factores de Edad , Animales , Castración , Femenino , Riñón/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Factores SexualesRESUMEN
During pregnancy, mice are more susceptible to flurothyl-induced seizures than are nonpregnant control mice. The potential role of brain GABA in mediating this behavior was examined in the present study. GABA concentrations in the cerebellum, hippocampus, striatum, midbrain, and cortex from individual control, pregnant (days 17-18) and delivery-day Heterogeneous Stock mice were assayed using a fluorometric method. Turnover of GABA was assessed by inhibiting metabolism with aminooxyacetic acid and measuring GABA accumulation over the next 2 h. Steady-state GABA concentrations decreased significantly from control in all brain regions during pregnancy. Reductions in GABA concentrations were approximately 25-30% in the affected regions. At parturition, GABA concentrations in the cerebellum and cortex returned to control levels, but hippocampal, striatal, and midbrain GABA levels remained significantly depressed. All the indices of GABA turnover--first-order rate constant, half-life, initial rate of synthesis, and turnover rate (product of first-order rate constant and initial concentration)--showed a significant reduction in pregnancy, which was continued through the time of delivery in all brain regions except the hippocampus. Half-life values for GABA increased nearly fourfold in the cerebellum and cortex. These results show that there is a significant alteration in GABAergic systems during pregnancy and parturition. We suggest that the reduction in GABA turnover is a compensatory anticonvulsant mechanism to offset the inherent seizure susceptibility brought about by the reduced level of the major inhibitory neurotransmitter in the brain.
Asunto(s)
Química Encefálica/fisiología , Preñez/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido Aminooxiacético/metabolismo , Animales , Encéfalo/enzimología , Femenino , Semivida , Ratones , EmbarazoRESUMEN
The long-sleep (LS) and short-sleep (SS) mice were selectively bred for differences in sensitivity to the depressant effects of ethanol. In addition to their differential sensitivity to ethanol, they are also differentially sensitive to purinergic agonists and antagonists. This suggests that there may be differences in the purinergic systems of these lines of mice which may aid in understanding how they differ in ethanol sensitivity. We have investigated whether these drugs are capable of modifying acute ethanol sensitivity as measured by ethanol-induced loss of the righting response (ethanol sleep time), waking blood and brain ethanol concentrations, and blood ethanol elimination rate. The purinergic agonists cyclohexyladenosine (CHA), L-phenylisopropyladenosine (PIA), 2-chloroadenosine (CAD), and N-ethylcarboxamidoadenosine (NEC) increased sleep time in both LS and SS mice, however, LS mice were generally more affected than SS. The LS and SS mice were also differentially sensitive to the purinergic antagonists, theophylline and caffeine. Blood and brain ethanol concentration on awakening suggested that CNS sensitivity to acute ethanol administration was altered by pretreatment with agonists but not antagonists. Two agonists, CHA and NEC, significantly lowered ethanol elimination in both lines of mice while PIA, CAD, and the antagonists theophylline, and caffeine were without affect on elimination rate. These data support previous observations that adenosine-mediated systems may be involved in the modulation of ethanol sensitivity.
Asunto(s)
Etanol/farmacología , Receptores Purinérgicos/efectos de los fármacos , Sueño/efectos de los fármacos , 2-Cloroadenosina/farmacología , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Análisis de Varianza , Animales , Encéfalo/metabolismo , Cafeína/farmacología , Relación Dosis-Respuesta a Droga , Etanol/sangre , Etanol/metabolismo , Femenino , Masculino , Ratones , Fenilisopropiladenosina/farmacología , Antagonistas Purinérgicos , Teofilina/farmacologíaRESUMEN
Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20-21, 30 +/- 1 and 65 +/- 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.
Asunto(s)
Envejecimiento/metabolismo , Cocaína/metabolismo , Microsomas Hepáticos/enzimología , Animales , Colinesterasas/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Microsomas Hepáticos/efectos de los fármacos , Oxidorreductasas N-Desmetilantes/metabolismo , Oxigenasas/metabolismo , Caracteres Sexuales , Especificidad de la EspecieRESUMEN
Cocaine may be metabolized either by ester hydrolysis to inactive products or by oxidation via a cytochrome P-450 and FAD-monooxygenase pathway to a hepatotoxic metabolite, presumably norcocaine nitroxide. Mice are the species most susceptible to cocaine-induced hepatotoxicity (CIH), and marked strain differences in response have been found. Female mice are very resistant to CIH, whereas males are susceptible, indicating that hormonal factors may be involved. We treated mice of 5 inbred strains with cocaine at three ages: 20 days (weanling), 30 days (adolescent) and 60 days (adult). The CIH response was assessed by measurement of plasma alanine aminotransferase (ALT) activity 18 hours later. For each of the strains females of all three age groups were resistant to CIH, and males did not begin to develop CIH until approximately 30 days of age. The degree of CIH in 30-day-old males was intermediate between the levels found in 20-day-old males and adult males. These data suggest that the enzyme, or enzymes, responsible for the production of the toxic metabolite are absent, or at very low levels, in female and immature male mice, and that they are either inducible by androgens or are repressed by estrogens or progestins. It is possible that these enzymes may be involved in the production of toxic metabolites of compounds other than cocaine.
Asunto(s)
Envejecimiento/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Cocaína/toxicidad , Alanina Transaminasa/sangre , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cocaína/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos , Factores Sexuales , Especificidad de la Especie , Factores de TiempoRESUMEN
The effects of chronic ethanol administration on vitamin B-6 metabolism were studied in female Long-Sleep (LS) and Short-Sleep (SS) mice. Animals were fed an ethanol containing liquid diet (AIN-76) for four weeks. Concentration of ethanol in the diet increased from 10 to 25% ethanol-derived calories (EDC) during weeks 1-3 and was maintained at 30% EDC for 1 additional week. We measured concentrations of pyridoxal 5'-phosphate (PLP) in plasma, erythrocytes and whole blood, and liver and brain PLP and pyridoxamine 5'-phosphate (PMP) in ethanol-fed and pair-fed control mice. Chronic ethanol administration significantly increased PMP and total (PLP + PMP) levels in the liver of SS mice. In LS mice ethanol feeding significantly decreased PMP and total (PLP + PMP) levels in the brain, but these values were still within normal limits. These results suggest that both control and ethanol-containing liquid diets are nutritionally adequate with respect to vitamin B-6, and that chronic ethanol administration does not adversely affect vitamin B-6 metabolism in adult mice.
Asunto(s)
Encéfalo/metabolismo , Etanol/farmacología , Hígado/metabolismo , Fosfato de Piridoxal/sangre , Piridoxamina/análogos & derivados , Animales , Ingestión de Energía , Eritrocitos/metabolismo , Etanol/administración & dosificación , Femenino , Ratones , Ratones Mutantes , Peromyscus , Fosfato de Piridoxal/metabolismo , Piridoxamina/sangre , Piridoxamina/metabolismo , Piridoxina/metabolismoRESUMEN
Ethanol is metabolized primarily in the liver by a cytosolic alcohol dehydrogenase (ADH). The product, acetaldehyde, is metabolized to acetate by nonspecific aldehyde dehydrogenases (AHD). Mouse liver contains five major constitutive AHD isoenzymes: mitochondrial high Km (AHD-1), mitochondrial low Km (AHD-5), cytosolic high Km (AHD-7), cytosolic low Km (AHD-2) and microsomal high Km (AHD-3). The Long-Sleep (LS) and Short-Sleep (SS) mice differ in their sleep time response to ethanol as early as 10 days of age, and this difference increases with increasing age. Age- and genotype-related differences in metabolism could account for the pattern of responses seen in these mice. We measured the activity of hepatic ADH and the five AHD isoenzymes in LS and SS mice from 3 days of age to adulthood to determine if there were differences in the developmental profiles of these enzyme activities. We found no sex differences in the developmental profile of either ADH or AHD, and the LS and SS mice have nearly identical ADH and AHD activities with the possible exception of the high Km mitochondrial enzyme activity between days 3 and 6, and the low Km mitochondrial enzyme between days 28 and 32. Thus, it appears that differences in ethanol or acetaldehyde metabolism do not contribute significantly to the differential sensitivity to ethanol between young LS and SS mice or to the differential sensitivity between young and adult mice.
Asunto(s)
Alcohol Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa/metabolismo , Etanol/farmacología , Isoenzimas/metabolismo , Hígado/enzimología , Sueño/efectos de los fármacos , Envejecimiento , Animales , Citosol/enzimología , Femenino , Genotipo , Hígado/crecimiento & desarrollo , Masculino , Ratones , Ratones Mutantes , Microsomas Hepáticos/enzimología , Mitocondrias Hepáticas/enzimologíaRESUMEN
Ethanol metabolism was measured in long-sleep (LS) and short-sleep (SS) mice on two occasions separated by 1 week to test for repeatability. Mice were injected intraperitoneally with either 1.5 or 4.0 g/kg ethanol and the linear decline of blood ethanol level was measured. The parameters measured in each animal were linear ethanol elimination rate (EER), peak blood ethanol level, volume of distribution and Widmark ratio (r). Reproducibility was assessed using two statistical methods, paired t tests and Pearson correlations. Paired t tests indicated good reproducibility since the two replicate determinations did not differ significantly from each other. The other widely used indicator of reproducibility, the correlation coefficient (Pearson r) between the two measurements, was nonsignificant in almost every case, indicating poor reproducibility. This occurs because the range of values of EER is fairly narrow; thus, an individual is likely to fall anywhere within that narrow range from one day to the next, and the rank ordering of the individuals may not be maintained. Although parameters such as EER and volume of distribution appear to be reproducible for populations, they may have little or no utility as covariates in genetic analyses of individual differences in response to ethanol.
Asunto(s)
Etanol/farmacocinética , Fases del Sueño/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Inyecciones Intraperitoneales , Masculino , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos , Factores de TiempoRESUMEN
It is often assumed that blood ethanol content accurately reflects brain ethanol content. In previous studies we have found that at the time of regaining the righting response blood and brain ethanol levels were identical, and blood ethanol could be used to predict brain ethanol level. It is likely, however that shortly after the administration of ethanol, blood and brain ethanol levels would differ. For this study, venous blood (orbital sinus) and brain ethanol levels were measured in long-sleep and short-sleep mice within the first 30 min following ethanol administration (2.5-6.0 g/kg). Ethanol was administered intraperitoneally or intragastrically. For both lines of mice and for every dose, brain ethanol concentrations were significantly greater (as much as 100 mg/dl) than blood ethanol levels for the first 6 min, and peak blood and brain ethanol levels were reached 4 to 6 min after dosing. Approximately 6 to 10 minutes (depending on dose and line of mouse) was required for blood and brain concentrations to reach equilibrium. At the time of loss of the righting response, brain ethanol levels were significantly higher than blood ethanol levels. These results indicate that within the first 6 min after administration of ethanol, blood ethanol level is not suitable for the assessment of brain ethanol content.
Asunto(s)
Química Encefálica/efectos de los fármacos , Etanol/metabolismo , Sueño/fisiología , Absorción , Animales , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Etanol/sangre , Inyecciones Intraperitoneales , Masculino , Ratones , Equilibrio Postural/efectos de los fármacosRESUMEN
Long sleep (LS) and short sleep (SS) lines of mice were derived from a heterogeneous stock of mice (HS) and have been selectively bred on the basis of the time the animals were devoid of the righting reflex (sleep time) following acute ethanol administration. We have tested a large group of the HS mice for sleep time response to ethanol. Animals were then selected from the extremes of the HS sleep time response and designated short sleep (HS-SS) or long sleep (HS-LS). The ED50 value for loss of righting reflex was compared between these mice (HS-SS and HS-LS) and animals that had undergone 25 generations of selection (SS and LS mice). The ED50 value was not significantly different for the HS-LS (1.9 g/kg) and LS (2.17 g/kg) mice but was markedly different between HS-SS (3.02 g/kg) and SS (4.21 g/kg) mice. The ED50 values for the eight inbred strains that constituted the HS stock ranged only from 2.33 to 2.78 g/kg. The value for LD50 one hour after ethanol administration was found to be 9.03 g/kg and for SS mice 6.94 g/kg for LS mice, in contrast to our previous findings of no difference in LD50 values between SS and LS mice when ascertained 24 hr after the ethanol dose. Since the two lines were selected only for a sleep time difference, a differential sensitivity to other consequences of acute ethanol exposure, such as the lethal dose, would not be expected unless the effects shared a common genetic mechanism of action with ethanol sleep time.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Etanol/farmacología , Sueño/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Etanol/sangre , Ratones , Ratones Endogámicos , Fenotipo , Sueño/fisiologíaRESUMEN
The mechanism underlying genetic variation in the acute and chronic responses of mice to diisopropylphosphofluoridate (DFP) are unknown. We investigated whether variation in metabolism of organophosphates by A-esterase, as exemplified by the enzyme paraoxonase, was correlated to the degree of sensitivity to DFP in four inbred mouse strains. LD50s and plasma paraoxonase were measured in each strain. We observed genetic variation in both of these measures, but there was no significant correlation between the two measures. We conclude that plasma paraoxonase activity does not underlie genetic variation in sensitivity to the lethal effects of DFP in mice since it does not determine the degree of sensitivity or resistance to DFP.
Asunto(s)
Isoflurofato/farmacología , Ratones Endogámicos/genética , Monoéster Fosfórico Hidrolasas/genética , Animales , Arildialquilfosfatasa , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Monoéster Fosfórico Hidrolasas/sangre , Factores SexualesRESUMEN
Male and female C57BL, DBA, and C3H mice were injected intraperitoneally with a single 6.33 mg/kg dose of diisopropylphosphofluoridate (DFP). The time course of recovery of acetylcholinesterase (AChE) activity as well as effects on choline acetyltransferase (ChAT) activity and brain muscarinic and nicotinic receptors were measured. DFP treatment did not affect ChAT activity or the muscarinic and nicotinic receptors. Near control levels of AChE activity were regained in female mice within the first 20 days. However, levels of whole brain AChE activity remained depressed for as long as 40 days following a single dose of DFP in male mice. An analysis of the recovery of AChE activity in several brain regions indicated that control activity was regained in striatum, hindbrain, and hippocampus, but not in cortex, midbrain, and hypothalamus. These data are discussed in terms of potential neurotoxicity induced by a single dose of DFP.
Asunto(s)
Acetilcolinesterasa/metabolismo , Encéfalo/efectos de los fármacos , Isoflurofato/toxicidad , Animales , Encéfalo/metabolismo , Colina O-Acetiltransferasa/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Factores Sexuales , Distribución TisularRESUMEN
During pregnancy mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The potential role of brain catecholamines in mediating this behavior was examined in the present study. The concentration and turnover of norepinephrine (NE) and dopamine (DA) were measured in hippocampus, striatum, midbrain and cortex in control, pregnant and delivery-day mice. There were no significant changes from control in DA levels during pregnancy and parturition. The turnover of DA was not altered during pregnancy, except for a small increase in turnover rate in the hippocampus. The concentration of NE decreased during pregnancy, and rose at parturition. This effect was most striking in the hippocampus. The turnover of NE was markedly depressed during pregnancy, with the hippocampus again being most affected. These data imply a role for NE, but not DA in the mediation of increased seizure susceptibility during pregnancy.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Norepinefrina/metabolismo , Preñez/metabolismo , Animales , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Femenino , Hipocampo/metabolismo , Trabajo de Parto/metabolismo , Mesencéfalo/metabolismo , Ratones , EmbarazoRESUMEN
In order to explore the relationship between response to muscarinic agonists and brain muscarinic receptors, two mouse strains that differ in acute sensitivity (DBA and C3H) were injected chronically with DFP or infused with oxotremorine. Chronic DFP-treated DBA mice were not tolerant to DFP's effects on any measure, but they were cross-tolerant to the effects of oxotremorine on heart rate and body temperature. DFP-treated C3H mice were not tolerant to DFP or cross-tolerant to oxotremorine on any measure. Oxotremorine infusion resulted in tolerance to oxotremorine in both mouse strains, and chronically infused DBA mice were cross-tolerant to DFP on five of the six measures. Oxotremorine-infused C3H mice were cross-tolerant to DFP on two of the measures. These results suggest that genetic factors influence the development of tolerance or cross-tolerance. These genetic factors do not seem to be related to changes in brain QNB binding. Both mouse strains showed comparable changes in QNB binding following chronic DFP and oxotremorine with DFP eliciting reductions in QNB binding in striatum and hippocampus and oxotremorine eliciting reductions in nearly every brain region. However, tolerance and cross-tolerance did not seem to correlate with changes in binding which suggests that the relationship between receptor changes and responses to muscarinic agonists must be examined further.
Asunto(s)
Isoflurofato/farmacología , Oxotremorina/farmacología , Receptores Muscarínicos/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Tolerancia a Medicamentos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos DBA , Actividad Motora/efectos de los fármacos , Quinuclidinil Bencilato/metabolismo , Especificidad de la EspecieRESUMEN
The duration of loss of the righting response (sleep time) is often used to assess central nervous system sensitivity to ethanol. It has been assumed that there is a threshold concentration of ethanol at which an animal will regain the righting response, and that this level should not change with dose or route of administration of ethanol. Five hypnotic doses of ethanol were given to Long-sleep and Short-sleep mice by intraperitoneal injection. At the time of awakening, blood and brain ethanol levels were measured. It was found that within a line, the animals awoke at the same blood and brain ethanol concentration irrespective of the ethanol dose given. The threshold blood ethanol level was 265 mg% for Long-Sleep males and 484 mg% for Short-Sleep males. These results indicate that there is a threshold value for ethanol, and that this threshold is characteristic for a given mouse line.
Asunto(s)
Etanol/farmacología , Ratones Endogámicos/genética , Vigilia/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Etanol/administración & dosificación , Etanol/análisis , Masculino , Ratones , Sueño/efectos de los fármacos , Factores de TiempoRESUMEN
The Long-Sleep (LS) and Short-Sleep (SS) mice were bred for differences in sensitivity to ethanol as measured by duration of loss of the righting response (sleep time). The foundation population was a heterogeneous stock (HS) which was derived from a cross of eight inbred strains. Ethanol-induced sleep time and waking blood and brain ethanol levels were measured in the eight inbred strains, LS, SS and HS mice. The C3H and ISBI strains were quite resistant to ethanol as measured by sleep time, and only one, RIII, was very sensitive. Waking ethanol concentrations were similar for all of the inbreds, implying a narrow range of central nervous system sensitivity to ethanol. The HS mice had relatively short sleep times and blood ethanol levels equal to most of the inbred. The LS mice were significantly more, and the SS mice significantly less sensitive to ethanol than any of the inbreds or HS mice. These studies suggest that the extremes of CNS sensitivities to ethanol manifested by the LS and SS mice cannot be traced to any of the inbred strains, and must have arisen through the selection process by changes in allelic frequencies of those genes conferring ethanol sensitivity and resistance.
Asunto(s)
Encéfalo/efectos de los fármacos , Etanol/farmacología , Sueño/efectos de los fármacos , Animales , Química Encefálica , Etanol/análisis , Femenino , Genética Conductual , Genotipo , Masculino , Ratones , Ratones Endogámicos , Sueño/fisiologíaRESUMEN
Several studies have demonstrated that chronic treatment with organophosphates, such as DFP, elicits a decreased number of brain muscarinic receptors (measured by the binding of QNB) which has been presented as an explanation for tolerance to the organophosphates. The purpose of the studies presented here was to assess whether graded changes in QNB binding could be attained following different methods of chronic DFP treatment, and whether tolerance to DFP paralleled these changes. Male DBA mice were injected with DFP every 4 days or 2 days for 30 days or daily for 14 days. The animals were subsequently challenged with DFP or the muscarinic agonist, oxotremorine, and respiratory rate, heart rate, body temperature, Y-maze activity and rearing were recorded. Chronic DFP-treated animals were supersensitive to the effects of DFP on respiratory rate, heart rate, and body temperature whereas a modest tolerance to the effects of oxotremorine on respiratory rate, heart rate, and body temperature was seen. Neither tolerance nor supersensitivity were observed for the effects of DFP and oxotremorine on the Y-maze measures. Chronic DFP treatment elicited reduced binding of QNB in striatum, cortex, and hippocampus with the group that had been treated every other day exhibiting the greatest changes. The changes in drug response did not parallel changes in QNB binding which raises questions as to the cause of the reduction in binding.
Asunto(s)
Encéfalo/efectos de los fármacos , Isoflurofato/farmacología , Receptores Muscarínicos/efectos de los fármacos , Animales , Temperatura Corporal/efectos de los fármacos , Encéfalo/metabolismo , Resistencia a Medicamentos , Tolerancia a Medicamentos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos DBA , Oxotremorina/farmacología , Quinuclidinil Bencilato/metabolismo , Receptores Muscarínicos/metabolismo , Respiración/efectos de los fármacosRESUMEN
In previous studies we have reported that flurothyl-induced clonic seizure threshold was significantly reduced in pregnant mice. In the present study eight strains of mice were tested for flurothyl seizure susceptibility during pregnancy in an effort to find one which lacked this trait. Latency to myoclonus, latency to clonus, and the interval between these seizures were measured. Two inbred strains, A/Ibg and BALB/cByJ, were resistant to the pregnancy-associated increase in seizure susceptibility. These strains will be used, along with others which show the increased seizure trait, to investigate the neurochemical mechanisms which underlie the increased seizure susceptibility in pregnancy.
Asunto(s)
Mioclonía/genética , Complicaciones del Embarazo , Convulsiones/genética , Animales , Susceptibilidad a Enfermedades , Femenino , Flurotilo , Genes , Ratones , Ratones Endogámicos A , Ratones Endogámicos BALB C , Ratones Endogámicos , Embarazo , Convulsiones/inducido químicamenteRESUMEN
Pregnant mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The possibility that the well-known increase in beta-endorphin concentration which accompanies pregnancy was involved in this effect was examined by testing whether naloxone administration could block the increased seizure susceptibility. Pregnant female, control female and male C3H mice were treated with 5-50 mg/kg naloxone 5 min before flurothyl seizure testing. Naloxone markedly increased clonic seizure susceptibility in all three groups at a dose of 50 mg/kg, but had little effect at lower doses. In contrast, naloxone had differential effects on myoclonic seizures in pregnant and control female mice, being anticonvulsant in the controls, but proconvulsant in the pregnant mice. A role for endogenous opiates is unlikely in mediating clonic seizures in pregnant mice, but may be involved in myoclonic seizures.
Asunto(s)
Endorfinas/fisiología , Naloxona/farmacología , Complicaciones del Embarazo , Convulsiones/etiología , Animales , Femenino , Flurotilo , Masculino , Ratones , Ratones Endogámicos C3H , Embarazo , Convulsiones/inducido químicamente , Convulsiones/fisiopatologíaRESUMEN
The effects of acute treatment with the organophosphate, diisopropylfluorophosphae (DFP), were studied in three inbred mouse strains. C57BL, DBA and C3H. A battery of physiological and locomotor tests including respiratory rate, heart rate, body temperature, Y-maze activity and rotarod performance was used. Dose-response and time course studies were carried out. Approximately 15 min after injection the animals were markedly affected by the drug with maximal effects occurring approximately 2 hours after injection. Strain comparisons were made at the 2 hr time point. In all strains, males and females were affected about equally except for respiratory rate and rotarod performance in which females were slightly more affected. Strain comparisons revealed that for most of the tests the C57BL mice were most affected by the DFP and the C3H mice were least affected. For the heart rate test the DBA mice were the most sensitive. Previous studies from our laboratory have demonstrated a similar rank ordering of the strains in their responses to oxotremorine and nicotine. The strain differences in response to these agents is not easily explained by differences in number or affinity of brain muscarinic or nicotinic receptors. The genetic influence on cholinergic drug response may involve receptor coupling mechanisms.